Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors.

BACKGROUND Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. METHODS [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys40(Ahx-DTPA-natIn)NH2]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. RESULTS Combination of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys40(Ahx-DTPA-111In)NH2]-exendin-4. CONCLUSION The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.

Neural circuits of emotion regulation: a comparison of mindfulness-based and cognitive reappraisal strategies

Dealing with one's emotions is a core skill in everyday life. Effective cognitive control strategies have been shown to be neurobiologically represented in prefrontal structures regulating limbic regions. In addition to cognitive strategies, mindfulness-associated methods are increasingly applied in psychotherapy. We compared the neurobiological mechanisms of these two strategies, i.e. cognitive reappraisal and mindfulness, during both the cued expectation and perception of negative and potentially negative emotional pictures. Fifty-three healthy participants were examined with functional magnetic resonance imaging (47 participants included in analysis). Twenty-four subjects applied mindfulness, 23 used cognitive reappraisal. On the neurofunctional level, both strategies were associated with comparable activity of the medial prefrontal cortex and the amygdala. When expecting negative versus neutral stimuli, the mindfulness group showed stronger activations in ventro- and dorsolateral prefrontal cortex, supramarginal gyrus as well as in the left insula. During the perception of negative versus neutral stimuli, the two groups only differed in an increased activity in the caudate in the cognitive group. Altogether, both strategies recruited overlapping brain regions known to be involved in emotion regulation. This result suggests that common neural circuits are involved in the emotion regulation by mindfulness-based and cognitive reappraisal strategies. Identifying differential activations being associated with the two strategies in this study might be one step towards a better understanding of differential mechanisms of change underlying frequently used psychotherapeutic interventions.

Prevalence of potential retrograde embolization pathways in the proximal descending aorta in stroke patients and controls.

BACKGROUND Retrograde diastolic blood flow in the proximal descending aorta (DAo) connecting complex plaques (≥4 mm thick) with brain-supplying supra-aortic arteries may constitute a source of stroke. Yet, data only from high-risk populations (cryptogenic stroke patients with aortic atheroma≥3 mm) regarding the prevalence of this potential stroke mechanism are available. We aimed to quantify the frequency of this mechanism in unselected patients with cryptogenic stroke after routine diagnostics and controls without a history of stroke. METHODS 88 patients (67 stroke patients, 21 cardiac controls) were prospectively included. 3D T1-weighted bright blood MRI of the aorta was applied for the detection of complex DAo atheroma. ECG-triggered and navigator-gated 4D flow MRI allowed measuring time-resolved 3D blood flow in vivo. Potential retrograde embolization pathways were defined as the co-occurrence of complex plaques and retrograde blood flow in the DAo reaching the outlet of (a) the left subclavian artery, (b) the left common carotid artery, or/and (c) the brachiocephalic trunk. The frequency of these pathways was analyzed by importing 2D plaque images into 3D blood flow visualization software. RESULTS Complex DAo plaques were more frequent in stroke patients (44 in 31/67 patients (46.3%) vs. 5 in 4/21 controls (19.1%); p=0.039), especially in older patients (29/46 (63.04%) patients≥60 years of age with 41 plaques vs. 2/21 (9.14%) patients<60 years of age with 3 plaques; p<0.001). Contrary to our assumption, retrograde diastolic blood flow at the DAo occurred in every patient irrespective of the existence of plaques with a similar extent in both groups (26±14 vs. 32±18 mm; p=0.114). Therefore, only the higher prevalence of complex DAo plaques in stroke patients resulted in a three times higher frequency of potential retrograde embolization pathways compared to controls (22/67 (32.8%) vs. 2/21 (9.5%) controls; p=0.048). CONCLUSIONS This study revealed that retrograde flow in the descending aorta is a common phenomenon not only in stroke patients. The existence of potential retrograde embolization pathways depends mainly on the occurrence of complex plaques in the area 0 to ∼30 mm behind the outlet of the left subclavian artery, which is exposed to flow reversal. In conclusion, we have shown that the frequency of potential retrograde embolization pathways was significantly higher in stroke patients suggesting that this mechanism may play a role in retrograde brain embolism.

Long-term outcome after arterial ischemic stroke in children and young adults.

OBJECTIVE To compare long-term outcome of children and young adults with arterial ischemic stroke (AIS) from 2 large registries. METHODS Prospective cohort study comparing functional and psychosocial long-term outcome (≥2 years after AIS) in patients who had AIS during childhood (1 month-16 years) or young adulthood (16.1-45 years) between January 2000 and December 2008, who consented to follow-up. Data of children were collected prospectively in the Swiss Neuropediatric Stroke Registry, young adults in the Bernese stroke database. RESULTS Follow-up information was available in 95/116 children and 154/187 young adults. Median follow-up of survivors was 6.9 years (interquartile range 4.7-9.4) and did not differ between the groups (p = 0.122). Long-term functional outcome was similar (p = 0.896): 53 (56%) children and 84 (55%) young adults had a favorable outcome (modified Rankin Scale 0-1). Mortality in children was 14% (13/95) and in young adults 7% (11/154) (p = 0.121) and recurrence rate did not differ (p = 0.759). Overall psychosocial impairment and quality of life did not differ, except for more behavioral problems among children (13% vs 5%, p = 0.040) and more frequent reports of an impact of AIS on everyday life among adults (27% vs 64%, p < 0.001). In a multivariate regression analysis, low Pediatric NIH Stroke Scale/NIH Stroke Scale score was the most important predictor of favorable outcome (p < 0.001). CONCLUSION There were no major differences in long-term outcome after AIS in children and young adults for mortality, disability, quality of life, psychological, or social variables.

Fetal megacystis: experience of a single tertiary center in Switzerland over 20 years

OBJECTIVES Megacystis (MC) is rare and often associated with other structural and chromosomal anomalies. In euploid cases with early oligohydramnios, prognosis is poor mainly due to pulmonary hypoplasia and renal damage. We report our experience of the past 20 years. METHODS A retrospective review of cases with prenatally diagnosed MC was performed. Complete prenatal as well as postnatal medical records from 1989 to 2009 were reviewed focusing on diagnostic precision, fetal interventions [vesicocentesis (VC), vesicoamniotic shunt (VAS)], short- and long-term outcome, and potential prognostic factors. RESULTS 68 cases were included. Follow-up was available in 54 cases (9 girls and 45 boys including 3 cases with aneuploidy). We found 39 isolated MC at sonography (5 girls and 34 boys). 24 fetuses with isolated MC underwent VC and VAS at 19.6 ± 6.3 and 20 ± 4.9 weeks of gestation, respectively. Survival rate was higher in male than in female fetuses (51 vs. 33%). Renal problems occurred in 4/14 prenatally treated fetuses and in 1/10 when cases with prune belly syndrome (PBS) were excluded from the analysis. CONCLUSIONS Our study shows that a careful selection of cases with MC excluding fetuses with PBS and early treatment has still the potential to improve outcome.

Pelvic floor muscle activation and strength components influencing female urinary continence and stress incontinence: A systematic review

AIMS A better understanding of pelvic floor muscle (PFM) activation and strength components is a prerequisite to get better insight in PFM contraction mechanisms and develop more specific PFM-training regimens for female stress urinary incontinence (SUI) patients. The aim of this systematic review (2012:CRD42012002547) was to evaluate and summarize existing studies investigating PFM activation and strength components influencing female continence and SUI. METHODS PubMed, EMBASE, and Cochrane databases were systematically searched for literature from January 1980 to November 2013 for cross-sectional studies comparing female SUI patients with healthy controls and intervention studies with SUI patients reporting on the association between PFM activation and strength components and urine loss. Trial characteristics, evaluated PFM components, their definitions, measurement methods, study outcomes, as well as quality measures, based on the Cochrane risk of bias tool, were independently extracted. The high heterogeneity of the retrieved data made pooling of results impossible and therefore restricted the analysis to a systematic review. RESULTS Cross-sectional studies showed group differences in favor of the continent women compared to SUI patients for PFM activation or PFM maximal strength, mean strength or sustained contraction. All intervention studies showed an improvement of PFM strength and decrease in urine loss in SUI patients after physical therapy. CONCLUSIONS Higher PFM activation and strength components influence female continence positively. This systematic review underscored the need for a standardized PFM components' terminology (similar to rehabilitation and training science), standardized test procedures and well matched diagnostic instruments. Neurourol. Urodynam. © 2014 Wiley Periodicals, Inc.

Arctic moisture source for Eurasian snow cover variations in autumn

Eurasian fall snow cover changes have been suggested as a driver for changes in the Arctic Oscillation and might provide a link between sea-ice decline in the Arctic during summer and atmospheric circulation in the following winter. However, the mechanism connecting snow cover in Eurasia to sea-ice decline in autumn is still under debate. Our analysis is based on snow observations from 820 Russian land stations, moisture transport using a Lagrangian approach derived from meteorological re-analyses. We show that declining sea-ice in the Barents and Kara Seas (BKS) acts as moisture source for the enhanced Western Siberian snow depth as a result of changed tropospheric moisture transport. Transient disturbances enter the continent from the BKS region related to anomalies in the planetary wave pattern and move southward along the Ural mountains where they merge into the extension of the Mediterranean storm track.

Influence of Gilbert's syndrome on the formation of ethyl glucuronide.

A drinking experiment with participants suffering from Gilbert's syndrome was performed to study the possible influence of this glucuronidation disorder on the formation of ethyl glucuronide (EtG). Gilbert's syndrome is a rather common and, in most cases, asymptomatic congenital metabolic aberration with a prevalence of about 5 %. It is characterized by a reduction of the enzyme activity of the uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 up to 80 %. One of the glucuronidation products is EtG, which is formed in the organism following exposure to ethanol. EtG is used as a short-term marker for ethyl alcohol consumption to prove abstinence in various settings. After 2 days of abstinence from ethanol and giving a void urine sample, 30 study participants drank 0.1 L of sparkling wine (9 g ethanol). 3, 6, 12, and 24 h after drinking, urine samples were collected. 3 hours after drinking, an additional blood sample was taken, in which liver enzyme activities, ethanol, hematological parameters, and bilirubin were measured. EtG and ethyl sulfate (EtS), another short-term marker of ethanol consumption, were determined in the urine samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS); creatinine was measured photometrically. In all participants, EtG and EtS were detected in concentrations showing a wide range (EtG: 3 h sample 0.5-18.43 mg/L and 6 h sample 0.67-13.8 mg/L; EtS: 3 h sample 0.87-6.87 mg/L and 6 h sample 0.29-4.48 mg/L). No evidence of impaired EtG formation was found. Thus, EtG seems to be a suitable marker for ethanol consumption even in individuals with Gilbert's syndrome.

Pandora's box and retrorectal tumors in laparoscopy: A case report and review of the literature.

INTRODUCTION Retrorectal tumors are uncommon and the etiology diverse. Literature to define the preoperative diagnosis and plan the intraoperative management are uncommon. PRESENTATION OF CASE We describe a case of a 44 year old patient with a laparoscopic approach for the removal of a retrorectal tumor and emphasize on the preoperative diagnostics and the intraoperative, minimal invasive approach. DISCUSSION Especially because these tumors are rare and often an incidental finding in gynecologic surgery, it is important to know the various differential diagnoses and its consequences with the laparoscopic approach. CONCLUSION We suggest the laparoscopic approach in cases of retroperitoneal cysts of unknown origin is ideal also because anatomic structures, mostly nerves, can be easily spared.